Thymoglobulin--new approaches to optimal outcomes.

Thymoglobulin has a proven safety and efficacy profile both as treatment of acute rejection and as induction therapy in organ transplantation. The most common adverse events associated with Thymoglobulin are cytokine release syndrome, thrombocytopenia, and lymphopenia. Results of early studies showed an increased rate of cytomegalovirus disease associated with Thymoglobulin treatment, but recent studies indicate that routine administration of modern antiviral prophylaxis can reduce this risk. More research comparing Thymoglobulin with basiliximab will help individualize regimens by matching the choice of induction agent with the risk profile of each transplant recipient. The proven efficacy and safety profile of Thymoglobulin provides an excellent starting point for future investigations. Horse ATG (hATG) or Thymoglobulin + Cyclosporine are an efficacious treatment for aplastic anemia. Due to its higher potency Thymoglobulin may be superior to hATG, but further studies are required for confirmation. GvHD prophylaxis with Thymoglobulin may result in less acute and chronic GvHD, lower TRM, improved survival and quality of life in myeloablative or reduced intensity conditioning protocols in patients receiving hematopoietic stem cells from related or unrelated donors. Attributable to its polyclonal nature, Thymoglobulin provides multifaceted immunomodulation suggesting that its use should be included in the immunosuppressant therapeutic armamentarium to help reduce the incidence of organ rejection and GvHD, and for treatment of aplastic anemia.


Introduction
Immunosuppressive properties of polyclonal antithymocyte globulins (ATG) were first described in the 1950s,[1] and ATG have been widely used for more than 30 years. [2] Recent findings demonstrate that ATG can provide a wide spectrum of immunomodulation, suggesting that their use in immunosuppression may help in reducing the incidence of organ rejection, improving patients' outcome after hematopoietic stem cell transplantation, [3] and treating autoimmune mediated disease, i.e. aplastic anemia.
ATG is a mixture of different antibody specificities, which induces an extremely effective dose-dependent T-cell depletion in blood and lymphoid tissues via complement-dependent cytotoxicity, antibody dependent cellular cytotoxicity, and apoptosis. [4] Currently there are three different ATGs commercially available: Human thymocytes are used as the immunogenic to produce Atgam ® (Pharmacia & Upjohn, NY, USA) in horses and Thymoglobulin ® (Genzyme Polyclonals, S.A.S. Marcy L'Etoile, France) in rabbits, respectively; a Jurkat cell line is used to produce ATG-Fresenius ® (Fresenius Biotech GmbH, Graefelfing, Germany) in rabbits. [4] Despite sharing some common properties, the commercially available ATG products are strictly different drugs.
[5] Immunosuppressive activity varies significantly from one preparation to the other, resulting in quite different dosages. Among these products, Thymoglobulin is probably the most potent, and the most extensively studied ATG. [5,6] This review describes the clinical use of Thymoglobulin in organ transplantation and hematology/oncology.

Mechanisms of action
The role of Thymoglobulin in the prevention and treatment of allograft rejection, graft versus-host disease (GVHD), and treatment of aplastic anemia

Solid organ transplantation: Prevention of rejection (induction)
The risk of organ rejection is bigger immediately (weeks to months) after transplantation. It declines during the first year and further on, but it is present through the whole life of the graft. 8 Thymoglobulin is indicated for prevention of graft rejection in organ transplantation (induction); dosage 1 to 1,5 mg/kg/day for 2 to 9 days (2 to 5 days in heart transplantation).
[9] In the US, antibody induction is used in the majority (>70%) of kidney and almost 50% of thoracic organ transplantations, and Thymoglobulin is the most frequently used induction agent.

Thymoglobulin induction versus no induction
In two randomized, prospective trials Thymoglobulin was shown to decrease the rate of acute rejection in kidney transplant patients compared to no induction (15,1% vs. 25,4%; 15,2% vs. 30,4% respectively, p<0.001 in both studies). In these early studies, the incidences of leucopenia, thrombocytopenia, fever, and cytomegalovirus infection were significantly higher in the Thymoglobulin groups. [11,12] A retrospective analysis in living donor kidney transplantation (n=214) in a single center versus a national cohort showed a significant benefit of Thymoglobulin induction vs. no antibody induction in a low risk patient population. Five years patient survival was 96% vs. 90% (p=0,03), and acute rejection at one year was 2% vs. 21% (p<0,001). Thymoglobulin was well tolerated with very few infections, and a low incidence of malignancy. [13]
[15] In a single-center, retrospective study Thymoglobulin induction (n=65) seemed to be connected with higher rates of CMV disease, malignancy, and death than ATG Fresenius (n=129).
[16] However limitations of this study are the variable doses of Thymoglobulin (17 -6 mg/kg total),[4] and lack of antiviral prophylaxis for the longest period of time. A retrospective analysis compared the long-term benefits of induction with Thymoglobulin (n=342) and ATG Fresenius (n=142) in heart transplantation from 1984 to 1996. Five year patient survival rate was significantly higher in the Thymoglobulin group (76% versus 60%; p<0,01); 72% versus 42% (p<0,01) of patients were free from acute rejection, less and less severe recurrent rejections were observed. Viral infections (53% vs. 39%; p<0,05), but not cytomegalovirus (CMV) infections (17% vs. 13%), were more frequently observed in the Thymoglobulin group. Post transplant lymphoproliferative disorders (PTLD) were comparable. The authors concluded, that the two rabbit ATGs have different immunosuppressive potency, and that Thymoglobulin is currently the most powerful induction agent in heart transplantation. [17]

Thymoglobulin versus anti-IL-2R antibodies
In a prospective, randomized trial comparing induction with Thymoglobulin (n=141)  A prospective study (n=150) showed excellent results of Thymoglobulin induction in a CNI-free maintenance and steroid-tapering protocol. Patients were randomized to either a sirolimusbased or a cyclosporine A (CsA) -based regimen. All patients received mycophenolate mofetil (MMF) and a 6-month course of corticosteroids. At the 12-months follow-up, 88% of patients were steroid free. No significant differences were observed in patient survival (97% in each treatment group), graft survival (90% vs. 93%) or acute rejection (14.3% vs. 8.6%). [23] In a retrospective study of cadaveric renal transplant recipients treated with Thymoglobulin (high immunological risk, n=30) or basiliximab (high and low risk n=115), maintenance with sirolimus and prednisone, and delayed introduction of reduced-dose CsA, BPAR at 3 months in high-immune responders was lower in patients receiving Thymoglobulin (3% vs. 26%; p=0.01). Serum creatinine was higher with basiliximab at 3, 6, and 12 months (p<0.02). Only Thymoglobulin showed an excellent result when CsA initiation was delayed for more than two weeks (0% vs. 24%).
[24] A single center trial of prednisone-free maintenance immunosuppression using Thymoglobulin induction and CsA/MMF or tacrolimus/sirolimus (TAC/SRL) in 589 patients showed an excellent five year patient and graft survival (91% and 84%), low incidence of acute rejection, and stable kidney function (serum creatinine 1,7±0,8 mg/dL). Steroid-related side effects like CMV infection and post transplant diabetes were minimized compared to the historic controls (p<0,0001). Thymoglobulin induction plus elimination of prednisone should be considered at least in low risk recipients. [25]

Treatment of steroid resistant acute rejection
Treatment of acute rejection requires a short course of more intensive immunosuppressive therapy. First-line therapy for acute rejection is usually high dose intravenous corticosteroids. In case of steroid resistant acute rejection alternative treatments are necessary, which can be either ATG or the monoclonal antibody muromonab-CD3 (OKT3 ® ; Ortho Biotech, Raritan NJ, USA). 26 Thymoglobulin is indicated for the treatment of graft rejection in organ transplantation with a recommended dosage of 1,5 mg/kg/day for 3 to 14 days.
[9] A double-blind randomized trial showed superiority of over Atgam in reversal of acute rejection (88% vs. 76% p=0,027) and prevention of recurrent rejection (17% vs. 36% p=0,011) in patients who received a renal transplant. Both drugs had a similar side effect profile. The enhanced clinical efficacy of Thymoglobulin was explained by higher affinity of rabbit IgG subtype to human lymphocytes, less batch-to-batch variability, longer half-life, and more profound and longer lasting lymphocyte depletion compared to horse ATG.
[27] Due to less frequent treatments of recurrent rejection and less frequent return to dialysis, Thymoglobulin provided significant cost savings. [

GvHD prophylaxis in allogenic HSCT
Both acute (a) and chronic (c) graft versus host disease (GvHD) are a major cause of transplant related morbidity and mortality after allogenic hematopoietic stem cell transplantation (HSCT). ATG have been used to reduce the risks of graft failure and GvHD. [43,44] Thymoglobulin is indicated for prophylaxis of acute and chronic graft versus host disease (GvHD), after hematopoietic stem cell transplantation; dosage is 2,5 mg/kg/day from day -4 to day -2 or -1.